The goals of the project ar to characterize the pathogenesis, natural history and therapy of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. Our clinical emphasis has been on oral and genital herpes and zoster. Analysis of 10 years of suppressive acyclovir therapy in patients with frequently recurring herpes have shown the drug to remain effective and well-tolerated. We developed and continue to test a model system in which ultraviolet light induces recurrent oral or sacral HSV infections in humans. In placebo-controlled trials topical sunblockers and acyclovir were found to significantly prevent uv-induced reactivation of HSV infection. We are now studying topical capsaicin, a substance P depleting agent to determine whether it will prevent recurrent oral herpes. A placebo-controlled trial showed that oral acyclovir significantly reduces rates of HSV1 outbreaks in patients with frequent oral recurrences. The major basic research thrust of our laboratory has been to define molecular aspects of HSV and VZV latency and pathogenesis. During the past year we completed one series of studies examining the nature and role of the latency-associated gene of HSV2. Mutant virus lacking only the promoter for this gene was shown to induce typical genital herpes in guinea pigs, but to have a markedly lower likelihood of reactivating. Specific VZV genes involved in latency and regulation are also examined. Genes 29 an 62 are expressed in human ganglia. The promoters, transcripts and regulation of these genes and VZV genes 4, 10, 28, 61 and 63 are being studied.